1. Technical Field of the Invention
This invention relates to a method for pain treatment. The method more particularly relates to administering histamine H4 receptor ligands or compositions comprising the same for treating various forms of pain as further described herein.
2. Description of Related Technology
Pain of various types and manifestations affects virtually all humans and animals. In the clinic, pain is the one of the most serious significant medical issues in health care, and affects the widest group of patients. A substantial number of medical disorders and conditions produce pain as part of the disorder or condition. The condition of pain can refer to various forms of pain, for example, inflammatory pain, post surgical pain, and neuropathic pain, among others.
Some methods for treating pain are currently known. Such methods typically involve the administration of a pharmaceutical agent that works through specific biological mechanisms to treat different pain states. However, significant drawbacks for available analgesic and antinociceptive agents exist. For example, selective and non-selective cyclooxygenase inhibitors have been associated with cardiovascular risks, gastric lesions, and bleeding side effects. Opioids have been associated with addiction, abuse liability, respiratory depression, and constipation. Moreover, even given such drawbacks, many current agents are only able to provide a partial or measured degree of relief against some forms of pain.
In particular, patients suffering from neuropathic pain are not well treated by any of the currently available drugs or by agents. Neuropathic pain can develop in response to previous injury or ongoing tissue injury, nerve injury, or diabetes. It is distinct from other types of pain (e.g. inflammatory pain) in that it persists long after signs of the original injury or damage have disappeared. Neuropathic pain also is associated with allodynia, hyperalgesia, or causalgia (Dworkin Clinical Journal of Pain (2002) vol. 18(6) pp. 343-9). Allodynia is the perception of pain following a stimulus that would not normally be painful. Hyperalgesia is an enhanced response to a mildly noxious stimulus. Causalgia is described as a chronic burning pain that shows persistence in the absence of obvious noxious stimuli.
In addition to neuropathic pain, there are other types of pain that are not inflammatory or not due to ongoing inflammation, including osteoarthritis pain, cancer pain, visceral pain.
Neuropathic pain is particularly difficult to treat and is not well treated with current therapies. The topic of neuropathic pain has been reviewed in the scientific literature, for example, Smith, et al. Drug Development Research (2001) vol. 54(3), pp. 140-153; Collins and Chessell Expert Opinion on Emerging Drugs (2005) vol. 10(1), pp. 95-108; Vinik and Mehrabyan Medical Clinics of North America (2004), vol. 88(4), pp. 947-999; Dray, Urban, and Dickenson Trends in Pharmacological Sciences (1994) vol. 15(6) pp. 190-7; Dworkin Clinical Journal of Pain (2002) vol. 18(6) pp. 343-9. As such, it would be particularly beneficial to identify new methods for treating pain and, more particularly, neuropathic pain. It would be particularly beneficial if such methods are based on previously unexplored mechanisms for pain treatment that may offer improved pain relief or are less associated with side effects.
Histamine is understood to modulate a number of physiological activities, acting through specific histamine receptors (reviewed in Parsons and Ganellin, British Journal of Pharmacology (2006) 147, S127-S135; Igaz and Hegyesi, in Histamine: Biology and Medical Aspects (2004), 89-96; Editor(s): A. Falus; Pub. S. Karger A G, Basel). Four histamine receptors have been identified to date as playing distinct physiological roles. These are the histamine H1 receptor, the histamine H2 receptor, the histamine H3 receptor, and the histamine H4 receptor. The histamine H4 receptor is the most recently identified histamine receptor and has been characterized as a distinct histamine receptor; it is found in a number of mammalian tissues and has been found to modulate a number of physiological processes, including immunological function.
The histamine H4 receptor (also alternately known herein as the H4 receptor) is a member of the 7-transmembrane G-protein coupled receptor (GPCR) family, and is located on the cell surface membrane, where it binds to the endogenous molecule histamine, and transduces signals that modulate specific cellular activities. General aspects of the histamine H4 receptor, its pharmacology, and known ligands of the H4 receptor have been reviewed in de Esch, et al. (Trends in Pharmacological Science (2005), v. 26, pp. 462-469). The human histamine H4 receptor is distinct from other human histamine receptors, has low protein sequence homology with other human histamine receptors: 23% primary amino acid sequence identity with the histamine H1 receptor, 22% primary amino acid sequence identity with the histamine H2 receptor, and 31% primary amino acid sequence identity with the histamine H3 receptor. The H4 receptor was reported by Nakamura, et al. (Biochemical and Biophysical Research Communications (2000), v. 279, pp. 615-620), and was subsequently cloned by numerous research groups (e.g. Nakamura, ibid.; Coge, et al., Biochemical and Biophysical Research Communications (2001) v. 284, pp. 301-309; Liu, et al. Molecular Pharmacology (2001) v. 59, pp. 420-426; Morse, et al. Journal of Pharmacology and Experimental Therapeutics (2001), v. 296, pp. 1058-1066; Nguyen, et al. Molecular Pharmacology (2001), v. 59, pp. 427-433; Zhu, et al. Molecular Pharmacology, (2001), v. 59, pp. 434-441). For an overview of the early efforts on cloning and characterization of histamine H4 receptors see Hough, Molecular Pharmacology, (2001), v. 59, pp. 415-419.
A search for H4 receptor cDNA by RTPCR (reverse transcriptase polymerase chain reaction) of cellular and tissue mRNA located H4 cDNA in various cells and tissues (Nakamura, ibid.). This has been confirmed in additional studies locating H4 cDNA in cells such as leukocytes, eosinophils, mast cells, dendritic cells, and basophils, (Nakamura, ibid.; de Esch, ibid.; Ling, et al. British Journal of Pharmacology (2004) 142, 161-171). Furthermore, H4 cDNA has been identified in several tissues, prominently bone marrow, spleen, lymph nodes, but also in heart, kidney, liver, lung, pancreas, skeletal muscle, leukocyte, prostate, small intestine, testis, and also in different brain regions ((Nakamura, ibid; de Esch, ibid; Coge, ibid).
Study of histamine H4 ligands in animal disease models, as well as in in vitro and ex vivo studies, have demonstrated that the histamine H4 receptor plays an important role in various physiological and pathophysiological processes. For example, in experiments with histamine H4 deficient (knock out) animals and cells and tissues from such histamine H4 deficient animals, the histamine H4 receptor has been demonstrated to play an important role in various physiological and pathophysiological processes. However, study of diseases and disorders where histamine H4 receptors have been found to play an important role predominantly have been related to, for example, asthma, allergy, rheumatoid arthritis, and inflammation.